Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer.

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

PDT-Enhanced Ferroptosis by a Polymer Nanoparticle with pH-Activated Singlet Oxygen Generation and Superb Biocompatibility for Cancer Therapy.

In this study, we reported a nanocomplex (PAF) of PEGylated polygalacturonic acid, 5,10,15,20-tetrakis (4-aminophenyl) porphyrin (TAPP), and Fe3+ for photodynamic therapy (PDT)-enhanced ferroptosis in cancer treatment. PAF exhibited a size of 135 nm and a TAPP and Fe3+ loading content of 6.99 and 0.77%, respectively. The singlet oxygen (1O2) generation capacity of TAPP can be activated and significantly enhanced at acidic pH (4.5-5.0). Besides, the enhanced near-infrared absorption of TAPP at acidic pH enabled a further increase in 1O2 generation capability by a near-infrared laser (760 nm). The polysaccharide-based polymer carrier offers excellent biocompatibility, and PAF displayed a proliferative effect in both normal (L929) and cancer (B16) cells. However, upon light irradiation, PAF exhibited high toxicity to B16 melanoma cells by intracellular reactive oxygen species elevation, glutathione depletion, and lipid peroxidation. PAF displayed a much better anticancer effect than the nanocomplex containing Fe3+ or TAPP alone, indicating the PDT-enhanced ferroptosis in PAF. This study suggested that PDT-enhanced ferroptosis could be a facile and robust strategy of nanotherapeutics with high potency, tumor selectivity, and excellent biocompatibility.

Tumor-pH-Sensitive PLLA-Based Microsphere with Acid Cleavable Acetal Bonds on the Backbone for Efficient Localized Chemotherapy.

Nanoparticle- and microsphere-based drug delivery systems (DDSs) have attracted wide attention in cancer therapy; those DDSs that are responsive to tumor environment can selectively identify tumor and normal tissues and therefore have shown enhanced anticancer efficacy and alleviated systemic toxicity. Here, tumor-pH-sensitive polymeric microspheres, which are prepared by multiblock poly(l-lactide) with pH-sensitive acetal bonds in the backbone, are employed to efficiently load water-soluble anticancer drug doxorubicin hydrochloride (DOX·HCl, drug loading content: ∼10%). The pH-sensitive DOX-loaded hollow microspheres were in the size range 2-10 µm and exhibited acid-accelerated degradation of polymer matrix and drug release, and thereby efficient in vitro cancer cell inhibition. The microspheres were further intratumorally injected into breast-tumor-bearing mice, and the in vivo anticancer experiment showed that pH-sensitive DOX-loaded microsphere showed better antitumor efficiency and prolonged life-span than its counterpart that does not have pH-responsive property. Moreover, negligible organ toxicity, especially cardiotoxicity that generally exists in DOX-involved chemotherapy where DOX is administrated by intravenous injection, was observed for DOX-loaded microspheres. Hence, tumor-pH-sensitive polymeric microspheres have appeared to be a simple and efficient platform for delivering hydrophilic anticancer drug with excellent anticancer efficacy and low systemic toxicity.

Cinnamaldehyde-Based Poly(ester-thioacetal) To Generate Reactive Oxygen Species for Fabricating Reactive Oxygen Species-Responsive Nanoparticles.

Due to the high oxidative stress of the tumor microenvironment, more and more researchers have been devoted to reactive oxygen species (ROS)-responsive nanodrug delivery systems for anticancer therapy. Herein, a ROS-responsive moiety, thioacetal, was synthesized, and cinnamaldehyde (CA) was introduced in the polymer chain to trigger the generation of ROS to expect the enhancement of the ROS-responsive effect. The poly(ester-thioacetal) mPEG2k - b-(NTA-HD)12 polymer, its self-assembled micelles, and the ROS-responsive behavior were characterized by 1H NMR and DLS. The anticancer drug doxorubicin (DOX) was adopted to prepare DOX-loaded poly(ester-thioacetal) micelles. The intracellular ROS detection indicated that the mPEG2k - b-(NTA-HD)12 polymer could degrade via the high concentration of ROS in cancer cells, and the released CA stimulated mitochondria to regenerate additional ROS. The flow cytometry results indicated that the ROS-responsive polymeric micelles showed faster cellular uptake compared to the control mPEG2k - b-PCL5k micelles. The ROS responsive DOX/mPEG2k - b-(NTA-HD)12 micelles exhibited much better anticancer efficiency on both 4T1 and HeLa cancer cells than DOX/mPEG2k - b-PCL5k micelles.

Synthesis and Antibacterial Study of Sulfobetaine/Quaternary Ammonium-Modified Star-Shaped Poly[2-(dimethylamino)ethyl methacrylate]-Based Copolymers with an Inorganic Core.

Cationic polymethacrylates are interesting candidates for bacterial disinfectants since they can be made in large-scale by various well-established polymerization techniques such as atom transfer radical polymerization (ATRP). However, they are usually toxic or ineffective in serum and various strategies to improve their biocompatibility or nonfouling property have often resulted in compromised bactericidal activity. Also, star-shaped polymers are less explored than linear polymers for application as antibacterial compounds. In this paper, star polymers with poly[2-(dimethylamino)ethyl methacrylate] (PDMA) as the arms and polyhedral oligomeric silsesquioxane (POSS) as the core (POSS-g-PDMA) were successfully synthesized by ATRP. The minimum inhibition concentrations (MICs) of the synthesized POSS-g-PDMA are in the range of 10-20 µg/mL. POSS-g-PDMA was further modified by various hydrophilization strategies in attempting to reduce hemolysis. With quaternization of POSS-g-PDMA, the antibacterial activities of the obtained quaternary polymers are almost unchanged and the copolymers become relatively nonhemolytic. We also copolymerized sulfobetaine (SB) with POSS-g-PDMA to obtain random and block PDMA-co-PSB arm structures, where the PDMA and poly(sulfobetaine) were the cationic and zwitterionic blocks, respectively. The random cationic-zwitterionic POSS-g-(PDMA-r-PSB) copolymers showed poor antibacterial activity, while the block POSS-g-(PDMA-b-PSB) copolymers retained the antibacterial and hemolytic activity of the pristine POSS-g-PDMA. Further, the block copolymers of POSS-g-(PDMA-b-PSB) showed enhanced antifouling property and serum stability as seen by their nanoparticle size stability in the presence of serum and reduced red blood cell aggregation; the POSS-g-(PDMA-b-PSB) also somewhat retained its MIC in blood unlike the quaternized or random zwitterionic copolymers. The antibacterial kinetics study showed that Escherichia coli can be killed within 30 min by both random and block copolymers of POSS-g-(PDMA-co-PSB). Finally, our POSS star polymers showed low toxicity to zebrafish embryo and could be potentially used in aquaculture antibacterial applications.

A ROS-responsive polymeric micelle with a π-conjugated thioketal moiety for enhanced drug loading and efficient drug delivery.

As the implications of reactive oxygen species (ROS) are elucidated in many diseases, ROS-responsive nanoparticles are attracting great interest from researchers. In this work, a ROS sensitive thioketal (TK) moiety with a π-conjugated structure was introduced into biodegradable methoxy poly(ethylene glycol)-thioketal-poly(ε-caprolactone)mPEG-TK-PCL micelles as a linker, which was designed to speed up the drug release and thus enhance the therapeutic efficacy. The micelle showed a high drug loading content of 12.8% and excellent stability under physiological conditions because of the evocation of π-π stacking and hydrophobic interactions with the anticancer drug doxorubicin (DOX). The polymeric micelle presented a better drug carrier capacity and higher in vitro anticancer efficacy towards cancer cells. The in vivo study showed that DOX-loaded mPEG-TK-PCL micelles displayed lower toxicity towards normal cells and remarkably enhanced antitumor efficacy. This research provides a way to design potential drug carriers for efficient cancer chemotherapy.

An Engineered Butyrate-Derived Polymer Nanoplatform as a Mucosa-Healing Enhancer Potentiates the Therapeutic Effect of Magnolol in Inflammatory Bowel Disease.

Colonic epithelial damage and dysregulated immune response are crucial factors in the progression and exacerbation of inflammatory bowel disease (IBD). Nanoenabled targeted drug delivery to the inflamed intestinal mucosa has shown promise in inducing and maintaining colitis remission, while minimizing side effects. Inspired by the excellent antioxidative and anti-inflammatory efficacy of naturally derived magnolol (Mag) and gut homeostasis regulation of microbiota-derived butyrate, we developed a pH/redox dual-responsive butyrate-rich polymer nanoparticle (PSBA) as an oral Mag delivery system for combinational therapy of IBD. PSBA showed a high butyrate content of 22% and effectively encapsulated Mag. The Mag-loaded nanoparticles (PSBA@Mag) demonstrated colonic pH and reduction-responsive drug release, ensuring efficient retention and adhesion in the colon of colitis mice. PSBA@Mag not only normalized the level of reactive oxygen species and inflammatory effectors in inflamed colonic mucosa but also restored the epithelial barrier function in both ulcerative colitis and Crohn's disease mouse models. Importantly, PSBA promoted the migration and healing ability of intestinal epithelial cells in vitro and in vivo, sensitizing the therapeutic efficacy of Mag in animal models. Moreover, transcriptomics and metabolism analyses revealed that PSBA@Mag mitigated inflammation by suppressing the production of pro-inflammatory cytokines and chemokines and restoring the lipid metabolism. Additionally, this nanomedicine modulated the gut microbiota by inhibiting pathogenic Proteus and Escherichia-Shigella and promoting the proliferation of beneficial probiotics, including Lachnoclostridium, Lachnospiraceae_NK4A136_group and norank_f_Ruminococcaceae. Overall, our findings highlight the potential of butyrate-functionalized polymethacrylates as versatile and effective nanoplatforms for colonic drug delivery and mucosa repair in combating IBD and other gastrointestinal disorders.

Harnessing polymer-derived drug delivery systems for combating inflammatory bowel disease.

The inflammatory bowel disease (IBD) is incurable, chronic, recrudescent disorders in the inflamed intestines. Current clinic treatments are challenged by systemic exposure-induced severe side effects, inefficiency after long-term treatment, and increased risks of infection and malignancy due to immunosuppression. Fortunately, naturally bioactive small molecules, reactive oxygen species scavengers (or antioxidants), and gut microbiota modulators have emerged as promising candidates for the IBD treatment. Polymeric systems have been engineered as a delivery vehicle to improve the bioavailability and efficacy of these therapeutic agents through targeting the mucosa and enhancing intestinal adhesion and retention, and reduce their systemic toxicity. Herein we survey polymer-derived drug delivery systems for combating the IBD. Advanced delivery technologies, therapeutic intervention strategies, and the principles for the construction of hierarchical, mucosa-targeting, and bioresponsive systems are elaborated, providing insights into design and development of from-bench-to-bedside drug delivery polymeric systems for the IBD treatment.

A reactive oxygen species-replenishing coordination polymer nanomedicine disrupts redox homeostasis and induces concurrent apoptosis-ferroptosis for combinational cancer therapy.

Reactive oxygen species (ROS) are important signal molecules and imbalanced ROS level could lead to cell death. Elevated ROS levels in tumor tissues offer an opportunity to design ROS-responsive drug delivery systems (DDSs) or ROS-based cancer therapies such as chemodynamic therapy. However, their anticancer efficacies are hampered by the ROS-consuming nature of these DDSs as well as the high concentration of reductive agents like glutathione (GSH). Here we developed a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde (CA)-based ROS-replenishing organic ligand (TCA). TCA can ROS-responsively release CA to supplement intracellular ROS and deplete GSH by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitated efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies revealed that ROS-replenishing PCFD exhibited much better anticancer effect than ROS-consuming control nanoparticle PAFD. The ingenious ROS-replenishing strategy could be expanded to construct versatile ROS-responsive DDSs and ROS-based nanomedicines with potentiated anticancer activity. STATEMENT OF SIGNIFICANCE: We develop a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde-based reactive oxygen species (ROS)-replenishing organic ligand. This functional ligand can ROS-responsively release cinnamaldehyde to supplement intracellular H2O2 and deplete glutathione (GSH) by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitates efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies reveal that ROS-replenishing PCFD exhibit much better anticancer effect than ROS consuming counterpart. This study provides a facile and straightforward strategy to design ROS amplifying nanoplatforms for cancer treatment.

Thermosensitive polymer hydrogel as a physical shield on colonic mucosa for colitis treatment.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), is a chronic disease characterized by diffuse mucosal inflammation limited to the colon. Topical drug delivery systems that could be facilely performed and efficiently retained at colon sites are attractive for clinical IBD treatment. Herein, we report the exploration of an injectable thermosensitive copolymer hydrogel as a topical formulation for IBD treatment and demonstrate its feasibility in UC treatment by shielding ulcer sites from the external environment and being a drug reservoir for sustained release. Poly(aliphatic ester)-based triblock copolymer, poly(dl-lactic acid)-poly(ethylene glycol)-poly(dl-lactic acid) (PDLLA-PEG-PDLLA), adopts the solution state at room temperature yet a gel state at body temperature when the polymer concentration is more than 11%. The gel acts not only as a physical mucosal barrier for protecting ulcer sites from microorganisms like bacteria but also as a mesalazine depot for enhanced drug retention in the colon for localized, sustained drug release. In vivo UC treatment reveals that blank gel as a mucosal protector shows nearly the same treatment effect to mesalazine SR granules. Mesalazine-loaded gel significantly suppresses inflammation and has the best outcomes of indices such as colonic length, mucosal injury index, pathological tissue, and inflammatory factor. The injectable thermosensitive polymer hydrogel represents a novel, robust platform for the efficient treatment of IBD by acting as a physical shield to block out the pro-inflammatory factors as well as a drug depot for enhanced drug retention and controlled delivery.

A double-layer dura mater based on poly(caprolactone-co-lactide) film and polyurethane sponge: preparation, characterization, and biodegradation study.

Synthetic, biodegradable polymers hold great potential in dura mater substitution. In this study, a dura mater-mimetic double-layer film@sponge composite was developed. The composite contains a poly(caprolactone-co-lactide) (PCLA) film and polyurethane (PU) sponge, which simulates the hard and soft layers of dura mater, respectively. PCLA films were prepared by a solution-casting method and showed excellent mechanical properties and tolerance to water. PU sponge was hydrophilic and had a high water-absorption rate (about 500%). The double-layer composite (film@sponge) integrated the good mechanical properties of the films and the good water absorption of the sponge. The excellent biocompatibility and biodegradability of the PCLA film@PU sponge composites were verified by in vitro degradation and cytotoxicity study and the in vivo implantation in the back of rats. Importantly, the film@sponge composite had a suitable degradation rate and good biocompatibility, holding potential in the field of dural repair.

A tumor extracellular pH-sensitive PD-L1 binding peptide nanoparticle for chemo-immunotherapy of cancer.

Chemo-immunotherapy is a promising model for the combination treatment of cancer. Many solid tumors overexpress programmed cell death ligand (PD-L1) for immune suppression. In this study, a PD-L1 binding peptide conjugate (DCS) nanoparticle with tumor extracellular pH-responsiveness was developed for efficient chemo-immunotherapy of colon cancer. A hydrophilic D-type polypeptide (D-PPA) and two hydrophobic stearyl chains were linked with a pH-sensitive linker to obtain amphiphilic DCS, which could self-assemble into nanoparticles (NPs). Anticancer agent doxorubicin (DOX) was loaded to obtain DOX@DCS NPs, which could accumulate at the tumor site by enhanced permeability and retention effect and release D-PPA at tumor extracellular pH. The release of D-PPA could not only lead to instability and aggregation of NPs for enhanced tumor retention but also block PD-1/PD-L1 to avoid immune escape and elicit enhanced immune response. In addition, DOX could induce immunogenic cell death (ICD) of cancer cells and promote anti-tumor immune response with the combination of PD-1/PD-L1 blocking. DOX@DCS showed efficient inhibition of CT26 tumors and induced immune response both in vitro and in vivo. Overall, our study reported a facile yet robust nanosystem based on an immune blocking peptide and a chemotherapeutic ICD inducer for efficient chemo-immunotherapy of cancer.

Redox-responsive polyethyleneimine/tetrahedron DNA/doxorubicin nanocomplexes for deep cell/tissue penetration to overcome multidrug resistance.

Deep penetration of nanomedicines to cancer cells and tissues is a main obstacle to conquering multidrug resistant (MDR) cancer. Here, we presented redox-responsive polyethyleneimine (disulfide cross-linked PEI, PSP)/tetrahedral DNA (TDNs)/doxorubicin (DOX) nanocomplexes (NCs), PSP/TDNs@DOX NCs, to accomplish tumor cell/tissue penetration for overcoming MDR. The NCs can respond to glutathione and DNase I to disassociate and release DOX. In vitro study revealed that the NCs (N/P = 30) with positive charge could be associated to cell membranes and "dig holes" on them, evoking the membrane-breaking for enhanced cellular internalization and bypassing endocytosis regardless of drug-resistant mechanism. Transwell and 3D tumor models study established that NCs can efficiently depart from cells through "holes leakage" and "infected" surrounding cells to penetrate into deep tumor tissues. In vivo study showed that the PSP/TDNs@DOX NCs exhibited superior tumor penetration and therapeutic efficiency in xenografted drug-resistant tumor mouse models including human breast (MCF-7/R) and ovarian (SKOV3/R) cancer, which represent MDR with characteristics of DOX efflux and impermeability, respectively.

Combination of PEG-decorated black phosphorus nanosheets and immunoadjuvant for photoimmunotherapy of melanoma.

Photoimmunotherapy, which combines local photothermal therapy (PTT) with immunological stimulation, is a promising modality for cancer treatment. Herein, we have reported a photothermal-immunotherapy of melanoma using pegylated black phosphorus nanosheets (BP-PEG NSs) and imiquimod (R837) as the photothermal conversion agent and the immunoadjuvant, respectively. The photothermal stability of BP NSs was remarkably enhanced after the modification of poly(ethylene glycol) (PEG) by electrostatic interactions. The in situ generation of tumor-associated antigens by PTT elicited a strong immune response in the presence of R837, achieving a photoimmunotherapy of B16 melanoma. This photoimmunotherapy stimulated a stronger immune response both in vitro and in vivo than monotherapy, inducing a much greater release of cytokines such as IL-6, IL-12, and TNF-α. In vivo antitumor studies in B16 tumor-bearing mice demonstrated that photoimmunotherapy showed the best tumor inhibition effects. Our study suggested that BP-PEG NS-based PTT primed with an immunoadjuvant can be used for synergistic photoimmunotherapy of melanomas.

Poly(ester-thioether) microspheres co-loaded with erlotinib and α-tocopheryl succinate for combinational therapy of non-small cell lung cancer.

Polymer microspheres are attracting wide attention in localized cancer therapy owing to the excellent biocompatibility and drug loading capacity, controllable biodegradation speeds, and minimized systemic toxicity. Herein, we presented poly(ester-thioether) microspheres, porous and nonporous, as drug depots for localized therapy of non-small cell lung cancer (NSCLC). Specifically, erlotinib and α-tocopheryl succinate (α-TOS), which are respectively an epidermal growth factor receptor (EGFR) inhibitor and mitochondria destabilizer, were efficiently loaded into porous and nonporous poly(ester-thioether) microspheres for the treatment of EGFR-overexpressing NSCLC (A549 cells). The poly(ester-thioether) microspheres significantly improved the bioavailability of both erlotinib and α-TOS in comparison to the free drug combination, realizing synergistic inhibition of A549 cells both in vitro and in vivo. The porous microspheres displayed faster degradation and drug release than the nonporous counterpart, thereby showing better anticancer efficacy. Overall, our study reported a new anticancer strategy of erlotinib and α-TOS combination for therapy of NSCLC, and established that poly(ester-thioether) microspheres could be a robust and biodegradable reservoir for drug delivery and localized cancer therapy.

Leveraging a polycationic polymer to direct tunable loading of an anticancer agent and photosensitizer with opposite charges for chemo-photodynamic therapy.

Herein, we reported a primary amine containing polycationic polymer to load an oppositely charged anticancer drug (doxorubicin, DOX) and a photosensitizer (chlorin e6, Ce6) for combinational chemo-photodynamic therapy. The electrostatic interactions as well as other multiple interactions between the polymer and payloads endowed the drug-loaded nanoparticles with excellent stability. Moreover, the electrostatic attraction between the cationic polymer and anionic Ce6 dictated that Ce6 had higher loading efficiency than DOX. DOX showed pH-responsive drug release owing to the increased solubility of protonated DOX and reduced interaction with the partially protonated polymer under acidic conditions. In contrast, Ce6 showed pH-insensitive release because of the smaller change in solubility and the intense interactions between Ce6 and the polymer. Synergistic chemo/photodynamic therapy of 4T1 cancer cells was achieved by light-triggered reactive oxygen species (ROS)-mediated enhanced cellular uptake and effective endo/lysosomal escape of drug-loaded nanoparticles. Our study demonstrated that the polycationic polymer could act as a robust carrier for differential loading and release of oppositely charged cargos for combinational therapy.

The polymerization kinetics, oxidation-responsiveness, and in vitro anticancer efficacy of poly(ester-thioether)s.

Biodegradable and stimuli-responsive polymers have been widely explored due to their great potential in various biomedical applications. Here, biodegradable and oxidation-responsive poly(ester-thioether)s with different backbones were prepared by polymerization of dithiols and diacrylates. Two isomeric dithiol monomers, 2,3-dimercaptobutane (DMB) and 1,4-butanedithiol (BDT), were employed to synthesize poly(ester-thioether)s in the presence of 1,6-hexanediol diacrylate (HDA). The polymerization and oxidation kinetics of poly(ester-thioether)s were found to be controllable by tuning the polymer backbones, which were prepared using different monomers. The polymerization kinetics demonstrated that BDT showed a faster polymerization rate than DMB due to less steric hindrance. Poly(ester-thioether)s PHBD and PHDM, which were prepared from BDT and DMB with HDA, respectively, showed the fastest and slowest oxidation-responsiveness both in THF solution and in the form of polymer films. Finally, the potential application of poly(ester-thioether)s as drug vehicles for anticancer therapy was confirmed by using doxorubicin (DOX) as a model drug. The DOX-loaded micelle DOX/mPEG-PHBD showed much faster H2O2-responsive drug release and better anticancer efficacy in both MCF-7 and 4T1 cells due to the higher sensitivity of PHBD to H2O2.

Polymer Structure-Guided Self-Assisted Preparation of Poly(ester-thioether)-Based Hollow Porous Microspheres and Hierarchically Interconnected Microcages for Drug Release.

Porous polymer microspheres (PPMs) have been widely applied in various biomedical fields. Herein, the self-assisted preparation of poly(ester-thioether)-based porous microspheres and hierarchical microcages, whose pore sizes can be controlled by varying the polymer structures, is reported. Poly(ester-thioether)s with alkyl side chains (carbon atom numbers were 2, 4, and 8) can generate hollow porous microspheres; the longer alkyl chain length, the larger pore size of microspheres. The allyl-modified poly(ester-thioether) (PHBDT-g-C3 ) can form highly open, hierarchically interconnected microcages. A formation mechanism of these PPMs is proposed; the hydrophobic side chains-mediated stabilization of oil droplets dictate the droplet aggregation and following solvent evaporation, which is the key to the formation of PPMs. The hierarchically interconnected microcages of PHBDT-g-C3 are due to the partially crosslinking of polymers. Pore sizes of PPMs can be further tuned by a simple mixing strategy of poly(ester-thioether)s with different pore-forming abilities. The potential application of these PPMs as H2 O2 -responsive vehicles for delivery of hydrophobic (Nile Red) and hydrophilic (doxorubicin hydrochloride) cargos is also investigated. The microspheres with larger pore sizes show faster in vitro drug release. The poly(ester-thioether)-based polymer microspheres can open a new avenue for the design of PPMs and provide a H2 O2 -responsive drug delivery platform.

Polymeric nanoparticles responsive to intracellular ROS for anticancer drug delivery.

Thioketal and thioether are moieties used to fabricate reactive oxygen species (ROS)-responsive polymers for drug delivery. In this paper, three amphiphilic copolymers of mPEG-poly(ester-thioether), mPEG-poly(thioketal-ester) and mPEG-poly(thioketal-ester-thioether) were synthesized. The ROS-responsive behaviors of the three copolymers nanoparticles as drug carriers were investigated. The ROS-sensitivity was demonstrated by NMR, DLS, and SEM. mPEG-poly(ester-thioether) nanoparticles exhibited the fastest drug release rate, which possessed the best ROS sensitivity. The in vitro anticancer activity of the DOX-loaded nanoparticles was studied, the results revealed that the mPEG-poly(ester-thioether) nanoparticles showed the most efficient anticancer activity. Notably, all the three ROS-responsive copolymers nanoparticles showed enhanced cellular uptake and anticancer efficacy comparing to the control mPEG-b-PCL nanoparticles.

Viral Capsids Mimicking Based on pH-Sensitive Biodegradable Polymeric Micelles for Efficient Anticancer Drug Delivery.

Bio-inspired supramolecular self-assembly have been widely explored in biomedical engineering, especially in the field of drug delivery. Here, viral capsid analogue pH-Sensitive polymeric micelles HA-Hyd-DOX were reported, where natural polysacarrides hyaluronic acid (HA) and anticancer drug doxorubicin (DOX), were linked through a hydrazone bond with a high drug loading content of 33.09 wt%. The polymeric micelles look like artificial virus capsids from "core-shell" structures. In addition, the polymeric backbone HA and hydrazone bonds were destroyed in the presence of hyaluronidase in cancer cells and under the acidic conditions of pH = 5 respectively, thereby prodrug-based polymeric micelles could penetrate into the tumor and DOX could be released in lysosomes to enhance anticancer efficacy. With the comparison of typical prodrug-based polymeric micelles mPEG-Hyd-DOX system where DOX was linked to methoxy poly(ethylene glycol) with a hydrazone bond linkage, HA-Hyd-DOX showed greater inhibition to cancer cells due to the better penetration. Such viral capsids mimicking polymeric micelles provided some remarkable benefits for drug delivery, including, high drug loading efficiency, controlled drug release and excellent biodegradable.